There are a number of compounds containing amines that are currently marketed as drugs. In certain circumstances, the presence of such functionality, however, can prevent effective drug delivery. This phenomenon could be due to a range of effects, including poor solubility and instability.
Inhaled drugs, however, have the potential to enter the systemic circulation and thereby circumvent a number of the problems associated with oral and other drug delivery methods. Moreover, by manipulation of particle size and/or density, delivery of drugs into the alveoli may be facilitated. Alveoli have a large surface area for drug absorption and are surrounded by an extensive capillary network which facilitates rapid passage of drugs into the pulmonary circulation. Furthermore, because blood returning from the lungs is pumped directly to the systemic arterial circulation, drugs inhaled into the alveoli have the potential to reach target organs very rapidly. Of particular importance is that drugs delivered in this manner reach their target site without being exposed to potentially degrading conditions in the gastrointestinal tract and without undergoing modification by first pass metabolism in the liver. Thus, it is desirable to provide a new route of administration for drug amines that rapidly produces peak plasma concentrations of the compounds. This invention provides a route of administration to accomplish this goal.
One type of inhalation aerosol is a condensation aerosol formed from vaporization of compounds. The use of vaporized drugs, thus, provides a method of maximizing alveolar delivery and rapidly delivering drugs to target organs. However, the heat required to vaporize a drug often also generates degradation products, which may decrease the efficacy of the thermal vapor and are undesirable to be delivered to the patient. Particularly, the salt form of a drug is expected to lower a compound's vapor pressure, and consequently raise its vaporization temperature and potentially increase the amount of degradation product that is likely generated. Thus, a method that enhances drug volatilization without the formation of a substantial amount of degradation products with amine drug salts and a method for selected amine drug salts suitable for use in condensation aerosol is needed. Therefore, one object of the invention is to provide a thermal vapor of amine drug salts for inhalation therapy that does not contain a significant amount of thermal degradation products.
Furthermore, while many drugs may be delivered in their free base form using vaporization, such as those, for example, disclosed in U.S. application Ser. No's: 10/150,591, 10/150,267, 10/155,705 and 10/152,640, some amine drugs are liquid in their free base form and thus, are not optimal in a vaporization method that uses films or coatings to generate the aerosol. In such cases, the physical or chemical stability of the coating may be enhanced through formation of the drug amine salt. Thus, another object of the present invention is to provide amine drugs with desirable properties for thermal vapor delivery.
While dry powder formulations and new liquid aerosol devices are being developed or are available for inhalation therapy. See for example, U.S. Pat. No. 5,993,805 to Sutton et al.; WO 0000176 to Robinson et al.; WO 9916419 to Tarara et al.; WO 0000215 to Bot et al.; U.S. Pat. No. 5,855,913 to Hanes et al.; and U.S. Pat. Nos. 6,136,295 and 5,874,064 to Edwards et al.; U.S. Pat. No. 6,131,570 to Schuster et al.; U.S. Pat. No. 5,724,957 to Rubsamen et al.; and U.S. Pat. No. 6,098,620 to Lloyd et al.; U.S. Pat. Nos. 5,586,550; 5,758,637; and 6,085,740 to Ivri et al.; and U.S. Pat. No. 5,938,117.
These technologies are limited, however. Dry powders require excipients to formulate the dry powders for appropriate delivery. Whereas with liquid aerosols, because the solubility of many drug compounds in water or other solvents suitable for liquid aerosol delivery is low, the total quantity of drug that can be delivered in a single breath is quite small. Thus, there is a need for condensation aerosol of amine drug salts that overcome these limitations. This invention provides such a means.
These and other features of the invention will be described in detail below. All publications, patents, and patent applications referred to herein are incorporated herein by reference in their entirety.